In recent years, leukocyte-free blood transfusion in which leukocytes contained in a blood product are removed in advance is increasingly applied in the field of blood transfusion. This is due to the finding that the side effects such as headache, nausea, chills, and an anhemolytic exothermic reaction, as well as heavy side effects such as alloantigen sensitization, post-blood transfusion graft versus host disease (GVHD), and virus infection are mainly induced by leukocytes contained in blood products used for the blood transfusion.
Methods for removing leukocytes from blood products are broadly classified into a centrifuge separation method, making use of differences in the specific gravity of blood components, and a filter method using a fiber material or a porous material having continuous pores as a filter material. The filter method is more popular due to higher leukocyte removing capability, simple procedure, lower cost, and the like.
Increasing recognition on the importance of blood transfusion using a leukocyte-free blood product in recent years has encouraged a desire for a leukocyte removal filter possessing more excellent leukocyte removing capability that can prevent the above-mentioned heavy side effects.
Since platelets are known to produce antiplatelet antibodies when blood transfusion is frequently conducted, development of the technology for removing platelets has also been desired to suppress production of antiplatelet antibodies. Conventionally, an effort of simultaneously removing leukocytes and platelets has been undertaken by decreasing the pore diameter of the filter, for example, by narrowing the space between fibers in the filter material so that platelets can be captured. However, decreasing the filter pore size results in a slow filtering speed, requiring a long time for removing leukocytes and platelets. Therefore, a technology for removing platelets at high efficiency at the time of removing leukocytes by a means other than decreasing the filter pore size has been desired.
To improve the leukocyte removal capability of a leukocyte removal filter, both physical factors and chemical factors of the filter must be taken into consideration.
The physical factors relate to the physical structure of the filter material such as a specific surface area, fiber diameter, void ratio, bulk density, and thickness in the case of fibrous media such as a nonwoven fabric, and a pore size, porosity, and thickness in the case of porous materials containing continuous pores. The physical factors of filter materials are commonly known to greatly contribute to the leukocyte removal capability of a filter. It is also known that the leukocyte removal capability can be improved by using a material with a high specific surface area, specifically by using super-fine fibers having a small fiber diameter, increasing a filling density, or decreasing a pore size.
The chemical factors, on the other hand, relate to denaturing or processing a filter material surface by, for example, causing a polymer to attach to the surface to increase the affinity with leukocytes or to improve wettability. In general, when blood is caused to come into contact with various polymers, blood acts differently according to the properties of the surface of the materials in terms of occurrence or nonoccurrence of blood clotting or cell activation. Although the reason for the above-described difference is still to be clarified, complicated mutual actions of the cells in blood with the material surface are thought to be one of the reasons (“Polymeric Materials For Medical Use” edited by Biomedical Polymer Material Editing Committee, 1981, Center for Academic Publications Japan).
If the denatured or processed surface of the material is viewed in terms of the hydrophilic or hydrophobic properties, a polymeric material with a hydrophilic surface exhibits only small surface energy with blood and small mutual interactions with proteins or blood cells, in general. For this reason, the polymeric material with a hydrophilic surface is reported to have a tendency of suppressing blood clotting and morphological change in blood cell (“Biomaterial Science” 2nd series, 135, 1982, Nankodo Co., Ltd.). Therefore, hydrophilic modification of the filter material used for blood processing is effective. Introducing hydrophilic monomers or polymers by graft polymerization or coating to the surface of the filter material is known as a technique known in the art.
WO 87/05812 (Japanese Patent Publication No. 6-51060) discloses a filter containing a nonionic hydrophilic group and a basic nitrogen-containing functional group on the surface and having a basic nitrogen atom content of 0.2-4.0 wt % in the circumferential surface area, and describes that the filter can efficiently remove leukocytes with only a slight amount of platelet loss. The patent specification also describes that the filter has leukocyte removal performance more excellent in comparison with conventional filters without coating (for example, Japanese Patent Publication No. 2-13587). EP 0606646 (KR 129767 and Japanese Patent Application Laid-open No. 6-246862) discloses a filter having leukocyte removal performance. The filter contains basic functional groups and nonionic hydrophilic groups on the surface at a molar ratio of the basic functional groups to the nonionic hydrophilic groups of 0.6-6 and has a density of the basic functional groups of 5×10−5 to 0.1 meq/m2.
However, if positively charged functional groups such as a dimethylamino group, diethylamino group, and quarternary ammonium salt are introduced at a high density together with nonionic hydrophilic groups onto the surface of a material, cells in blood products, in particular erythrocytes, are firstly adsorbed in the material on the surface and occupy the seats for leukocytes to be adsorbed, resulting in a tendency of preventing improvement in the leukocyte removal capability. In this manner, the conventional technique of surface modification with positively charged functional groups provides only a small effect on the selectivity in the adsorption of leukocytes and erythrocytes and has difficulty in providing the filter with high leukocyte removal capability. If the density of the positively charged functional groups is increased with an objective of increasing platelet removal capability, platelets may be undesirably activated inducing morphological change and the like. Such a material cannot be used as the coating material of the filter for simultaneous removal of leukocytes and platelets.
WO 89/03717 (Published Japanese Translation of PCT Application No. 3-502094) discloses a filter using a porous web with a critical wetting surface tension (CWST) of 53-90 dyn/cm produced by grafting 2-hydroxyethyl methacrylate (HEMA) with methyl acrylate (MA) or methyl methacrylate (MMA) and changing their proportion. This filter, however, is not suitable for efficiently removing platelets.
As an invention relating to a technology for efficiently removing not only leukocytes but also platelets, Japanese Patent Application Laid-open No. 2000-197814 discloses a hydrophilic coating material containing quaternary ammonium salt. However, leukocyte removal capability and platelet removal capability of these filters are not necessarily sufficient. Although the use of a quaternary ammonium salt remarkably promoted hydrophilic properties and the CWST of the filter technically exceeded the level achieved by WO 89/03717 (Published Japanese Translation of PCT Application No. 3-502094), the method requires a washing step after the coating step to reduce elution.
As an invention to remove not only leukocytes but also platelets efficiently, U.S. Pat. No. 5,498,336 (EP 500472, Japanese Patent No. 3124565, Japanese Patent Application Laid-open No. 6-142196, and Japanese Patent No. 3273061) discloses a porous filter material with a positive surface zeta potential comprising a substance having a cationic functional group such as an amino group incorporated in or bonded to the material and a means for avoiding clogging of the filter with leukocytes and platelets by providing the main filter on the blood outlet side with a plus zeta potential of the porous filter material and the main filter on the blood inlet side with a minus zeta potential. If the zeta potential is increased to increase the leukocyte adsorption capability, not only leukocytes and platelets are adsorbed, but also erythrocytes are adsorbed, resulting in a general tendency of an increase in the process pressure. The leukocyte removal capability of the filter declines with time. As a countermeasure against the pressure increase of the filter, a main filter having a negative zeta potential is provided as an upper layer with an objective of suppressing adsorption of leukocytes and platelets in the upper layer. Although this method can suppress the pressure and reduce leakage of leukocytes throughout the entire process time, the leukocyte removal capability and platelet removal capability are not yet sufficient.
Japanese Patent Application Laid-open No. 7-25776 discloses a filter material with less elution that can selectively remove leukocytes while maintaining high platelet permeability and high leukocyte removal capability, wherein the surface of the filter material is coated with a polymer having both a hydrophobic part and a polyethylene oxide chain. The patent specification presents polymerizable monomers having hydrophobic parts and a polymer for coating for leukocyte removal containing polyethylene oxide chains and basic nitrogen-containing functional groups. The hydrophobic parts are introduced to decrease elution, whereas the polyethylene oxide chains are introduced to increase permeability of platelets. The objectives differ from that of the objective of ensuring high leukocyte removal capability and high platelet removal capability at the same time in the present invention.